The BAF complex inhibitor pyrimethamine reverses HIV-1 latency in people with HIV-1 on antiretroviral therapy

• DOI: 10.1126/sciadv.ade6675
• Publication Date: 2023-03-15T17:58:42Z
• Authors: Henrieke A. B. Prins; Raquel Crespo; Cynthia Lungu; Shringar Rao; Letao Li; Ronald J. Overmars; Grigorius Papageo...; Yvonne M. Mueller; Mateusz Stoszko; Tanvir Hossain; Tsung Wai Kan; Bart J. A. Rijnders; Hannelore I. Bax; Eric C. M. van Gorp; Jan L. Nouwen; Theodora E. M. S....; Carolina A. M. Sc...; Mariana de Mendon...; Els van Nood; Angela Colbers; David Burger; Robert-Jan Palstra; Jeroen J. A. van ...; David A. M. C. va...; Thibault Mesplède; Peter D. Katsikis; Rob A. Gruters; Birgit C. P. Koch; Annelies Verbon; Tokameh Mahmoudi; Casper Rokx
• Keywords: CD4-Positive T-Lymphocytes; Valproic Acid; Radboud University Medical Center; HIV Infections; Virus Latency; 3. Good health; Pyrimethamine; SDG 3 - Good Health and Well-being; HIV-1; Humans; RNA; Radboudumc 4: lnfectious Diseases and Global Health Clinical Pharmacy; Virus Activation; Biomedicine and Life Sciences

Reactivation of the latent HIV-1 reservoir is a first step toward triggering reservoir decay. Here, we investigated the impact of the BAF complex inhibitor pyrimethamine on the reservoir of people living with HIV-1 (PLWH). Twenty-eight PLWH on suppressive antiretroviral therapy were randomized (1:1:1:1 ratio) to receive pyrimethamine, valproic acid, both, or no intervention for 14 days. The primary end point was change in cell-associated unspliced (CA US) HIV-1 RNA at days 0 and 14. We observed a rapid, modest, and significant increase in (CA US) HIV-1 RNA in response to pyrimethamine exposure, which persisted throughout treatment and follow-up. Valproic acid treatment alone did not increase (CA US) HIV-1 RNA or augment the effect of pyrimethamine. Pyrimethamine treatment did not result in a reduction in the size of the inducible reservoir. These data demonstrate that the licensed drug pyrimethamine can be repurposed as a BAF complex inhibitor to reverse HIV-1 latency in vivo in PLWH, substantiating its potential advancement in clinical studies.